Nicotine-containing pharmaceutical composition

ABSTRACT

A composition intended to be employed for therapeutic purposes incorporates a nicotinic compound, a sugar substitute, and a sugar alcohol syrup. Representative forms of nicotine include free base (e.g., as a mixture of nicotine and microcrystalline cellulose), a nicotine salt (e.g., as nicotine bitartrate) or nicotine polacrilex. The composition is useful for treatment of central nervous system conditions, diseases, and disorders, and as a nicotine replacement therapy.

FIELD OF THE INVENTION

The present invention relates to compositions that contain nicotine, andin particular, to nicotine-containing pharmaceutical compositionsintended to be administered to provide a pharmacological effect, orotherwise used for therapeutic purposes.

BACKGROUND OF THE INVENTION

Central nervous system (CNS) conditions, diseases, or disorders can bedrug induced; can be attributed to genetic predisposition, infection ortrauma; or can be of unknown etiology. They comprise neuropsychiatricdisorders, neurological diseases and mental illnesses; and includeneurodegenerative diseases, behavioral disorders, cognitive disordersand cognitive affective disorders. The clinical manifestations ofseveral CNS conditions, diseases or disorders have been attributed toCNS dysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors).

Nicotinic compounds, such as nicotine, are capable of affectingnicotinic acetylcholinergic receptors (nAChRs). Subtypes of nAChRs existin both the CNS and the peripheral nervous system (PNS), but thedistribution of subtypes is heterogeneous. For instance, certainsubtypes which are predominant in vertebrate brain, others predominateat the autonomic ganglia, and others predominate at neuromuscularjunction. Activation of nAChRs by nicotinic compounds results inneurotransmitter release. See, for example, Dwoskin et al., Exp. Opin.Ther. Patents, 10: 1561-1581 (2000); Schmitt et al., Annual Reports inMed. Chem. 35: 41-51 (2000); Huang et al., J. Am. Chem. Soc., 127:14401-14414 (2006); Arneric et al., Biochem. Pharmacol., 74: 1092-1101(2007) and Millar, Biochem. Pharmacol., 78: 766-776 (2009); which areincorporated herein by reference.

It has been suggested that administration of nicotine, and othernicotinic compounds, can result in various pharmacological effects. See,for example, U.S. Pat. Nos. 5,583,140 to Bencherif et al.; 5,723,477 toMcDonald et al.; 7,001,900 to Jacobsen et al.; 7,135,484 to Dart et al.and 7,214,686 to Bencherif et al.; and US Pat. Pub. No. 2010/0004451 toAhmad et al.; which are incorporated herein by reference. As a result,it has been suggested that nicotine, and other nicotinic compounds, canexhibit utility in the treatment of a wide variety of conditions,diseases, and disorders, including those that affect the CNS.Additionally, administration of nicotine and nicotinic compounds hasbeen proposed for treatment of certain other conditions, diseases, anddisorders. See, for example, U.S. Pat. Nos. 5,604,231 to Smith et al.;5,811,442 to Bencherif et al.; 6,238,689 to Rhodes et al.; and 6,489,349to Bencherif et al.; which are incorporated herein by reference.Furthermore, administration of nicotine has been employed in an effortto help cigarette smokers quit smoking (i.e., as a smoking cessationaid). For example, nicotine has been an active ingredient of varioustypes of so-called “nicotine replacement therapy” or “NRT” products.See, for example, U.S. patent application Ser. No. 12/769,335 andInternational Application No. PCT/US2011/033928, both to Brinkley etal., which are incorporated herein by reference.

It has been proposed to administer nicotine using a transdermal patch.Representative types of nicotine-containing transdermal patch productshave been marketed under the tradenames “Habitrol,” “Nicoderm,”“Nicorette,” “Nicorette CQ,” “Nicotinell” and “ProStep.” See also, forexample, U.S. Pat. Nos. 4,597,961 to Etscom; 5,298,257 to Bannon et al.;5,603,947 to Wong et al.; 5,834,011 to Rose et al.; 6,165,497 to Osborneet al. and 6,676,959 to Anderson et al., which are incorporated hereinby reference. It also has been suggested that transdermal administrationof nicotine can be accompanied by ingestion of other types ofnicotine-containing products. See, for example, U.S. Pat. No. 5,593,684to Baker et al.; US Pat. Pub. No. 2009/0004249 to Gonda; and Fagerstrom,Health Values, 18:15 (1994), which are incorporated herein by reference.

One particularly popular way to provide for oral administration ofnicotine has been through the use of nicotine-containing gum.Nicotine-containing gum products have been marketed under the tradenames“Nicorette,” “Nicotinell” and “Zonnic.” See also, for example, U.S. Pat.Nos. 3,845,217 to Ferno et al.; 3,877,468 to Lichtneckert et al.;3,901,248 to Lichtneckert et al.; 6,344,222 to Cherukuri et al.;6,358,060 to Pinney et al.; 6,773,716 to Ream et al. and 6,893,654 toPinney et al.; and US Pat. Pub. No. 2004/0191322 to Hansson, which areincorporated herein by reference.

Another way that has been employed to provide oral administration ofnicotine has been through the use of nicotine-containing lozenge ortablet types of products. Nicotine-containing lozenge, mini lozenge,tablet, and microtab types of products have been marketed under thetradenames “Commit,” “Nicorette,” “Nicotinell” and “NiQuitin.” See also,for example, U.S. Pat. Nos. 5,110,605 to Acharya; 5,733,574 to Dam;6,280,761 to Santus; 6,676,959 to Andersson et al. and 6,248,760 toWilhelmsen; US Pat. Pub. Nos. 2001/0016593 to Wilhelmsen and2010/0004294 to Axelsson et al., which are incorporated herein byreference.

Nicotine also has been administered in the form of nasal or oral sprays.Various exemplary ways to administer nicotine in the form of a nasalspray are set forth in U.S. Pat. Nos. 4,579,858 to Ferno et al.;5,656,255 to Jones and 6,596,740 to Jones, which are incorporated hereinby reference. Various exemplary ways to administer nicotine in the formof an oral spray, such as for buccal administration, are set forth inU.S. Pat. No. 6,024,097 to Von Wielligh; US Pat. Pub. Nos. 2003/0159702to Lindell et al.; 2007/0163610 to Lindell et al. and 2009/0023819 toAxelsson; EP 1458388 to Lindell et al.; and PCT WO 2008/037470 toAxelsson et al., which are incorporated herein by reference.Nicotine-containing sprays have been marketed under the tradenames“Nicotrol NS,” “Quit” and “Zonnic.”

Various other ways to administer nicotine for the purpose of providing atherapeutic effect have been proposed. For example, it has beensuggested that nicotine can be incorporated into orally dissolving films(e.g., U.S. Pat. Nos. 6,709,671 to Zerbe et al.; 7,025,983 to Leung etal.; and 7,491,406 to Leung et al.; and US Pat. Pub. Nos. 2006/0198873to Chan et al. and 2006/0204559 to Bess et al.); oral osmotic devices(e.g., U.S. Pat. No. 5,147,654 to Place et al.); gum pads (e.g., U.S.Pat. No. 6,319,510 to Yates); oral patches (e.g., US Pat. Pub. No.2006/0240087 to Houze et al.); snuff-type forms in pouches or sachets(e.g., U.S. Pat. No. 4,907,605 to Ray et al. and US Pat. Pub. No.2009/0293895 to Axelsson et al.); lip balm (e.g., U.S. Pat. No.7,105,173 to Rolling) and beverages (e.g., U.S. Pat. Nos. 6,268,386 toThompson; 7,115,297 to Stillman and 7,435,749 to Knight). It also hasbeen suggested that nicotine can be delivered using various types ofinhalation devices and vapor delivery systems (e.g., U.S. Pat. Nos.4,284,809 to Ray; 4,800,903 to Ray et al.; 6,234,169 to Bulbrook et al.and 6,874,507 to Farr; and US Pat. Pub. Nos. 2006/0018840 toLechuga-Ballesteros and 2009/0005423 to Gonda; and EP 1,618,803 to Hon).

It would be desirable to provide alternative compositions capable ofdelivering or administering nicotine via an oral route for therapeuticpurposes.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a nicotine-containingcomposition intended to be employed for therapeutic purposes. Thecomposition is typically in a pharmaceutically acceptable form adaptedfor oral delivery of the composition. The composition incorporates atleast one nicotinic compound, a sugar substitute, and a sugar alcoholsyrup. In certain embodiments, the composition exhibits some level oftranslucency.

In certain embodiments, the present invention provides anicotine-containing pharmaceutical composition, comprising: a nicotiniccompound; at least about 80% by weight of a sugar substitute; and asugar alcohol syrup, wherein the sugar substitute is a non-hygroscopicsugar alcohol capable of forming a glassy matrix and wherein thecomposition is in a pharmaceutically acceptable form adapted for oraldelivery of the composition. At least a portion of the nicotiniccompound can, in certain embodiments, be in the form of a free base, asalt, a complex, or a solvate. For example, the nicotinic compound maycomprise nicotine polacrilex. In some embodiments, the nicotiniccompound is sorbed onto a porous particulate carrier. For example, theporous particulate carrier can comprise microcrystalline cellulose.

In some embodiments, the sugar substitute is isomalt. In certainembodiments, the sugar alcohol syrup is maltitol syrup or xylitol syrup.The amount of the components can vary. For example, in some embodiments,the composition comprises at least about 85% by weight of the sugarsubstitute. In some embodiments, the amount of sugar alcohol syrup isthat amount sufficient to slow recrystallization of the sugar substitutein melted form. For example, in some embodiments, the compositioncomprises at least about 4.0% by weight or at least about 4.5% by weightof the sugar alcohol syrup.

Various components can be included within the pharmaceuticalcomposition. For example, in some embodiments, the composition furthercomprises one or more of flavorants, sweeteners, and NaCl. The amountand type of these components can vary. For example, in some embodiments,the amount of flavorant is from about 0.1 to about 0.5 percent by weightof the pharmaceutical composition. In some embodiments, the flavorant isvanillin and/or mint flavor. In some embodiments, the sweetenercomprises sucralose. The amount of NaCl, where included, may be fromabout 0.5 to about 1 percent by weight of the composition in certainembodiments.

The pharmaceutical composition may take any form. For example, in someembodiments, the composition is in the form of a lozenge or tablet. Incertain embodiments, the composition is translucent. In certainembodiments, the composition is transparent.

In another aspect of the invention is provided a method for treating ahuman subject having a condition, disease, or disorder responsive tostimulation of nicotinic acetylcholinergic receptors, comprising orallyadministering an effective amount of a pharmaceutical compositionaccording to any of the embodiments noted herein to a human subject(e.g., administering a nicotine-containing pharmaceutical composition,comprising: a nicotinic compound; at least about 80% by weight of asugar substitute; and a sugar alcohol syrup, wherein the sugarsubstitute is a non-hygroscopic sugar alcohol capable of forming aglassy matrix and wherein the composition is in a pharmaceuticallyacceptable form adapted for oral delivery of the composition). Forexample, the method may involve administering a composition thatincorporates a nicotinic compound, a sugar substitute, and a sugaralcohol syrup. The administering step can, in certain embodiments,comprise administering the pharmaceutical composition to a human subjecthaving a condition, disease, or disorder of the central nervous system.The administering step can, in certain embodiments, compriseadministering the pharmaceutical composition to a human subject as asmoking cessation aid.

In a further aspect, the invention provides a method of preparing anicotine-containing pharmaceutical composition, comprising mixing anon-hygroscopic sugar substitute capable of forming a glassy matrix inan amount of at least about 80% by weight and a sugar alcohol syrup, ina melted state to form a mixture; cooling the mixture and incorporatinga nicotinic compound into the cooled mixture; and further cooling themixture to room temperature to form a solid nicotine-containingpharmaceutical composition. Various other steps can be included withinthis method. For example, the method may, in certain embodiments,further comprise adding one or more components selected from the groupconsisting of flavorants, sweeteners, and NaCl.

In some embodiments, the mixing step comprises heating the sugarsubstitute and the sugar alcohol syrup to a temperature above the hardcrack stage of the sugar substitute and the incorporating step comprisesadding a nicotinic compound to the mixture at a temperature below thehard crack stage of the sugar substitute. For example, in certainspecific embodiments, the hard crack stage is about 145° C. to about155° C. and the sugar substitute and the sugar alcohol syrup are heatedat a temperature between the hard crack stage and about 171° C.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present inventions now will be described more fully hereinafter. Theinvention may be embodied in many different forms and should not beconstrued as limited to the embodiments set forth herein; rather, theseembodiments are provided so that this disclosure will satisfy applicablelegal requirements. As used in this specification and the claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise.

The present invention involves the use of nicotinic compounds fortherapeutic purposes and provides compositions adapted for oral deliveryof nicotinic compounds. As used herein, “nicotinic compound” refers tonaturally occurring or synthetic nicotine unbound from a plant material,meaning the compound is at least partially purified and not containedwithin a plant structure such as a tobacco leaf. Most preferably,nicotine is naturally-occurring and obtained as an extract from aNicotiana species (e.g., tobacco). Exemplary types of tobacco andmanners of processing the tobacco are set forth in U.S. patentapplication Ser. No. 13/095,277 to Byrd et al., which is incorporatedherein by reference.

The nicotine can have the enantiomeric form S(−)-nicotine,R(+)-nicotine, or a mixture of S(−)-nicotine and R(+)-nicotine. Mostpreferably, the nicotine is in the form of S(−)-nicotine (e.g., in aform that is virtually all S(−)-nicotine) or a racemic mixture composedprimarily or predominantly of S(−)-nicotine (e.g., a mixture composed ofabout 95 weight parts S(−)-nicotine and about 5 weight partsR(+)-nicotine). Most preferably, the nicotine is employed in virtuallypure form or in an essentially pure form. Highly preferred nicotine thatis employed has a purity of greater than about 95 percent, morepreferably greater than about 98 percent, and most preferably greaterthan about 99 percent, on a weight basis. Despite the fact that nicotinecan be extracted from Nicotiana species, it is highly preferred that thenicotine (and the composition and products produced in accordance withthe present invention) is virtually or essentially absent of othercomponents of tobacco.

In embodiments wherein nicotine is derived from a plant of the Nicotianaspecies, the plant or portions thereof can be subjected to various typesof processing conditions to provide the nicotine. For example,components can be separated from one another, or otherwise fractionatedinto chemical classes or mixtures of individual compounds. Typicalseparation processes can include one or more process steps (e.g.,solvent extraction using polar solvents, organic solvents, orsupercritical fluids), chromatography, distillation, filtration,recrystallization, and/or solvent-solvent partitioning. Exemplaryextraction and separation solvents or carriers include water, alcohols(e.g., methanol or ethanol), hydrocarbons (e.g., heptane and hexane),diethyl ether methylene chloride and supercritical carbon dioxide.Exemplary techniques useful for extracting components from Nicotianaspecies are described in U.S. Pat. Nos. 4,144,895 to Fiore; 4,150,677 toOsborne, Jr. et al.; 4,267,847 to Reid; 4,289,147 to Wildman et al.;4,351,346 to Brummer et al.; 4,359,059 to Brummer et al.; 4,506,682 toMuller; 4,589,428 to Keritsis; 4,605,016 to Soga et al.; 4,716,911 toPoulose et al.; 4,727,889 to Niven, Jr. et al.; 4,887,618 to Bernasek etal.; 4,941,484 to Clapp et al.; 4,967,771 to Fagg et al.; 4,986,286 toRoberts et al.; 5,005,593 to Fagg et al.; 5,018,540 to Grubbs et al.;5,060,669 to White et al.; 5,065,775 to Fagg; 5,074,319 to White et al.;5,099,862 to White et al.; 5,121,757 to White et al.; 5,131,414 to Fagg;5,131,415 to Munoz et al.; 5,148,819 to Fagg; 5,197,494 to Kramer;5,230,354 to Smith et al.; 5,234,008 to Fagg; 5,243,999 to Smith;5,301,694 to Raymond et al.; 5,318,050 to Gonzalez-Parra et al.;5,343,879 to Teague; 5,360,022 to Newton; 5,435,325 to Clapp et al.;5,445,169 to Brinkley et al.; 6,131,584 to Lauterbach; 6,298,859 toKierulff et al.; 6,772,767 to Mua et al.; and 7,337,782 to Thompson, allof which are incorporated herein by reference. See also, the types ofseparation techniques set forth in Brandt et al., LC-GC Europe, p. 2-5(March, 2002) and Wellings, A Practical Handbook of Preparative HPLC(2006), which are incorporated herein by reference. In addition, theplant or portions thereof can be subjected to the types of treatmentsset forth in Ishikawa et al., Chem. Pharm. Bull., 50, 501-507 (2002);Tienpont et al., Anal. Bioanal. Chem., 373, 46-55 (2002); Ochiai,Gerstel Solutions Worldwide, 6, 17-19 (2006); Coleman, III, et al., J.Sci. Food and Agric., 84, 1223-1228 (2004); Coleman, III et al., J. Sci.Food and Agric., 85, 2645-2654 (2005); Pawliszyn, ed., Applications ofSolid Phase Microextraction, RSC Chromatography Monographs, (RoyalSociety of Chemistry, UK) (1999); Sahraoui et al., J. Chrom., 1210,229-233 (2008); and 5,301,694 to Raymond et al., which are allincorporated herein by reference.

In certain embodiments, isolation of nicotine from a plant of theNicotiana species comprises a step of removing high molecular weightcomponents from a tobacco extract. In certain embodiments, highmolecular weight components that are beneficially removed according tothe present invention include, but are not limited to, high molecularweight Maillard browning polymers, proteins, polysaccharides, certainpigments, and bacteria. Various methods can be used for this purpose,including size exclusion chromatography, microfiltration,ultrafiltration, nanofiltration, reverse osmosis, and combinationsthereof.

In one embodiment, ultrafiltration is used to remove high molecularweight components from tobacco material. The ultrafiltration method istypically applied to a tobacco material in the form of a tobacco extract(e.g., an aqueous tobacco extract). In ultrafiltration, the material tobe filtered is brought into contact with a semipermeable membrane. Themembrane can be of any type, such as plate-and-frame (having a stack ofmembranes and support plates), spiral-wound (having consecutive layersof membrane and support material rolled up around a tube), tubular(having a membrane-defined core through which the feed flows and anouter, tubular housing where permeate is collected), or hollow fiber(having several small diameter tubes or fibers wherein the permeate iscollected in the cartridge area surrounding the fibers). The membranecan be constructed of any material. For example, polysulfone,polyethersulfone, polypropylene, polyvinylidenefluoride, and celluloseacetate membranes are commonly used, although other materials can beused without departing from the invention described herein.

Ultrafiltration membranes are available in a wide range of pore sizes(typically ranging from about 0.1 to about 0.001 microns). Membranes aremore typically described by their number average molecular weightcutoffs. Ultrafiltration membranes are commonly classified as membraneswith molecular weight cutoffs of from about 10³ Da to about 10⁵ Da. Inpractice, compounds with molecular weights above the molecular weightcutoff are retained in the retentate, and the compounds with molecularweights below the cutoff pass through the filter into the permeate.Ultrafiltration methods typically are not capable of removing lowmolecular weight organic compounds and ions.

Ultrafiltration is typically a cross-flow separation process. The liquidstream to be treated (feed) flows tangentially along the membranesurface, separating into one stream that passes through the membrane(permeate) and another that does not (retentate or concentrate). Theoperating parameters of the ultrafiltration system can be varied toachieve the desired result. For example, the feed mixture to be filteredcan be brought into contact with the membrane by way of appliedpressure. The rate of permeation across the membrane is directlyproportional to the applied pressure; however, the maximum pressure maybe limited. The flow velocity of the mixture across the membrane surfacecan be adjusted. Temperature can also be varied. Typically, permeationrates increase with increasing temperature.

Commercial ultrafiltration systems are readily available and may be usedfor the ultrafiltration methods of the present invention. For example,commercial suppliers such as Millipore, Spectrum® Labs, PallCorporation, Whatman®, Porex Corporation, and Snyder Filtrationmanufacture various filter membranes and cartridges, and/or filtrationsystems (e.g., tangential flow filtration systems). Exemplary membranesinclude, but are not limited to, Biomax® and Ultracel® membranes andPellicon® XL cassettes (from Millipore), Microkros®, Minikros®, andKrosFlo® Hollow Fiber Modules (from Spectrum® Labs), and Microza filtersand Centramate,™ Centrasette,™ Maximate™, and Maxisette™ Tangential FlowFiltration Membrane Cassettes. Commercially available filtration systemsinclude, but are not limited to, Millipore's Labscale™ Tangential FlowFiltration (TFF) system and Spectrum® Labs' KrosFlo® and MiniKros®Tangential Flow Filtration Systems.

Filters and/or membranes that may be useful according to the presentinvention include those with molecular weight cutoffs of less than about100,000 Da, less than about 75,000 Da, less than about 50,000, less thanabout 25,000 Da, less than about 20,000 Da, less than about 15,000 Da,less than about 10,000 Da, and less than about 5,000 Da. In certainembodiments, a multistage filtration process is used to provide anextract with improved clarity. Such embodiments employ multiple filtersand/or membranes of different (typically decreasing) molecular weightcutoffs. Any number of filters and/or membranes can be used insuccession according to the invention. For example, a first filtrationmay be conducted using a 50,000 Da molecular weight cutoff filter and asecond filtration may be conducted using a 5,000 Da molecular weightcutoff filter. Accordingly, the ultrafiltered extract can comprise onlycompounds with molecular weights below about 50,000, below about 25,000,below about 10,000 Da, below about 7,500 Da, below about 5,000 Da, belowabout 2,500 Da, or below about 1,000 Da. The ultrafiltered extracttypically comprises primarily sugars, nicotine, and amino acids.Ultrafiltration can be used in combination with other separation andpurification methods to provide nicotine having an acceptable puritylevel.

The ultrafiltered extract exhibits a level of improvement in clarityover the non-ultrafiltered extract. Clarity of the extract (andpharmaceutical compositions according to the invention made therefrom),is typically defined in terms of translucency. As used herein,“translucent” or “translucency” refers to materials allowing some levelof light to travel therethrough diffusely. In certain embodiments,certain materials of the invention (e.g., certain tobacco extracts orpharmaceutical compositions made therefrom) can have such a high degreeof clarity that the material can be classified as “transparent” orexhibiting “transparency,” which is defined as a material allowing lightto pass freely through without significant diffusion. The clarity of theultrafiltered extract is such that there is some level of translucencyas opposed to opacity (which refers to materials that are impenetrableby light).

The improvement in clarity of the ultrafiltered extract over thenon-ultrafiltered extract can be quantified by any known method. Forexample, optical methods such as turbidimetry (or nephelometry) andcolorimetry may be used to quantify the cloudiness (light scattering)and the color (light absorption), respectively, of the ultrafilteredextract or products made therefrom. Translucency can also be confirmedby visual inspection by simply holding the material (e.g., extract) orproduct up to a light source and determining if light travels throughthe material or product in a diffuse manner.

In certain embodiments, the ultrafiltered extract is analyzed bycontacting the extract with light and measuring the percent of lightthat has not been absorbed and/or dispersed by the extract. Themeasurement can be done, for example, using a standard spectrophotometerat a given wavelength. The spectrophotometer is typically calibratedwith deionized water, which is assigned a transparency value of 100%.Acceptable levels of translucency/transparency at a given wavelength inthe ultrafiltered extract can vary. Typically, the ultrafiltered extracthas a translucency of greater than about 5%, greater than about 10%,greater than about 15%, greater than about 20%, greater than about 25%,greater than about 30%, greater than about 40%, greater than about 50%,greater than about 60%, greater than about 60%, greater than about 70%,greater than about 80%, or greater than about 90%. Typically, theultrafiltered extract will not be colorless, and will have somediscernible brown/black coloring. Following ultrafiltration, the extractcan be stored in the refrigerator or freezer or the extract can befreeze dried or spray dried prior to further processing to isolate thenicotine therefrom for use in pharmaceutical compositions according tothe present invention.

Nicotinic compounds of the invention can include nicotine in free baseform, salt form, as a complex, or as a solvate. See, for example, thediscussion of nicotine in free base form in US Pat. Pub. No.2004/0191322 to Hansson, which is incorporated herein by reference. Atleast a portion of the nicotinic compound can be employed in the form ofa resin complex of nicotine where nicotine is bound in an ion exchangeresin such as nicotine polacrilex. See, for example, U.S. Pat. No.3,901,248 to Lichtneckert et al.; which is incorporated herein byreference. At least a portion of the nicotine can be employed in theform of a salt. Salts of nicotine can be provided using the types ofingredients and techniques set forth in U.S. Pat. No. 2,033,909 to Coxet al. and Perfetti, Beitrage Tabakforschung Int., 12, 43-54 (1983).Additionally, salts of nicotine have been available from sources such asPfaltz and Bauer, Inc. and K&K Laboratories, Division of ICNBiochemicals, Inc. Exemplary pharmaceutically acceptable nicotine saltsinclude nicotine salts of tartrate (e.g., nicotine tartrate and nicotinebitartrate) chloride (e.g., nicotine hydrochloride and nicotinedihydrochloride), sulfate, perchlorate, ascorbate, fumarate, citrate,malate, lactate, aspartate, salicylate, tosylate, succinate, pyruvate,and the like; nicotine salt hydrates (e.g., nicotine zinc chloridemonohydrate), and the like. In certain embodiments, at least a portionof the nicotinic compound is in the form of a salt with an organic acidmoiety, including, but not limited to, levulinic acid as discussed inU.S. patent application Ser. No. 12/769,335 and InternationalApplication No. PCT/US2011/033928, both to Brinkley et al., which areincorporated herein by reference.

In one embodiment, the nicotinic compound is sorbed onto a porousparticulate carrier material, such as microcrystalline cellulose (MCC)prior to incorporation within the compositions of the invention. In oneembodiment, the MCC materials used in the invention have an averageparticle size range of about 15 to about 250 microns. Exemplary MCCmaterials include various grades of AVICEL® and VIVACEL® materials. See,for example, US Pat. Pub. No. 2004/0191322 to Hansson, which isincorporated by reference herein. In certain embodiments, multiple formsof nicotinic compounds could be sorbed onto the particulate carrier,including any of the various nicotinic compound combinations discussedherein. In some embodiments, the nicotinic compound and, optionally, anorganic acid moiety can be sorbed onto the particulate carrier by, forexample, dissolving the nicotinic compound (and, optionally, an organicacid moiety) in a hydrophilic solvent (such as water, alcohol, ormixtures thereof) and combining the solution with the particulatecarrier, followed by drying to remove the solvent. The particulatecarrier material with the sorbed nicotine and, optionally, organic acidmoiety, can be combined with other carriers or excipients in order toprovide a composition adapted for oral delivery of the activeingredient.

The compositions of the invention possess a form that ispharmaceutically effective and pharmaceutically acceptable. That is, thecomposition most preferably does not incorporate to any appreciabledegree, or does not purposefully incorporate, components of tobacco,other than nicotine. As such, pharmaceutically effective andpharmaceutically acceptable compositions do not include tobacco,processed tobacco components, or many of the components of tobaccotraditionally present within tobacco-containing cigarettes, cigars,pipes, or smokeless forms of tobacco products. Highly preferredcompositions include less than 0.5 weight percent of tobacco componentsother than nicotine, more often less than about 0.25 weight percent, andtypically are entirely absent or devoid of components of tobacco,processed tobacco components, or components derived from tobacco, otherthan nicotine.

The pharmaceutical compositions of the invention may be convenientlymade available in a unit dosage form, whereby such formulations may beprepared by any of the methods generally known in the pharmaceuticalarts. Generally speaking, such methods of preparation comprise combining(by various methods) an active agent with a suitable carrier or otheradjuvant, which may consist of one or more ingredients. The combinationof the active ingredient with the one or more adjuvants is thenphysically treated to present the formulation in a suitable form fordelivery (e.g., shaping into a tablet or forming an aqueous suspension).

The nicotine-containing pharmaceutical compositions of the invention canincorporate various pharmaceutically acceptable excipients. By“pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” is intended a carrier or excipient that is conventionallyused in the art to facilitate the storage, administration, and/or thehealing effect of an active agent (e.g., a nicotinic compound). Thecarrier(s) must be pharmaceutically acceptable in the sense of beingcompatible with the other ingredients of the formulation and not undulydeleterious to the recipient thereof. A carrier may also reduce anyundesirable side effects of the agent. See, Wang et al. (1980) J.Parent. Drug Assn. 34(6):452-462, herein incorporated by reference inits entirety. Other exemplary pharmaceutical excipients and/or additivessuitable for use in the compositions according to the invention arelisted in Remington: The Science & Practice of Pharmacy, 21^(st) ed.,Lippincott Williams & Wilkins (2006); in the Physician's Desk Reference,64^(th) ed., Thomson PDR (2010); and in Handbook of PharmaceuticalExcipients, 6^(th) ed., Eds. Raymond C. Rowe et al., PharmaceuticalPress (2009), which are incorporated herein by reference.

The various excipients can vary, and the selection and amount of eachexcipient can depend upon factors such as the ultimate form and functionof product that is desired. See, for example, the types of ingredients,relative amounts and combinations of ingredients, nicotine-containingformulations and preparation processes for nicotine-containing productsset forth in U.S. Pat. Nos. 5,512,306 to Carlsson et al.; 5,525,351 toDam; 5,549,906 to Santus; 5,711,961 to Reiner et al.; 5,811,126 toKrishnamurthy; 5,939,100 to Albrechtsen et al.; 6,024,981 to Khankari etal.; 6,083,531 to Humbert-Droz et al.; 6,090,401 to Gowan, Jr. et al.;6,110,495 to Dam; 6,248,760 to Wilhelmsen; 6,280,761 to Santus;6,426,090 to Ream et al.; 6,569,463 to Patel et al.; 6,583,160 to Smithet al.; 6,585,997 to Moro et al.; 6,676,959 to Andersson et al.;6,893,654 to Pinney et al.; 7,025,983 to Leung et al.; and 7,163,705Johnson et al.; US Pat. Pub. Nos. 2003/0176467 to Andersson et al.;2003/0235617 to Martino et al.; 2004/0096501 to Vaya et al.;2004/0101543 to Liu et al.; 2004/0191322 to Hansson; 2005/0053665 to Eket al.; 2005/0123502 to Chan et al.; 2008/0038209 to Andersen et al.;2008/0286341 to Andersson et al.; 2009/0023819 to Axelsson; 2009/0092573to Andersen; 2010/0004294 to Axelsson et al.; and 2010/0061940 toAxelsson et al.; which are incorporated herein by reference.

Although sucrose can be used in the preparation of thenicotine-containing products of the present invention, the products aretypically sugar-free products, comprising one or more sugar substitutes.“Sugar-free” as used herein is intended to include products having lessthan about 1/15th sugar by weight, or less than about 1/10th sugar byweight.

In certain embodiments, the base of the nicotine products describedherein is a sugar substitute. By “base” is meant a substance that makesup a relatively high percentage of the nicotine product. The amount ofsugar substitute in the nicotine-containing product mixture can vary,but is typically at least about 60%, at least about 75%, at least about80%, at least about 85%, or at least about 90% by weight of the mixture.

The sugar substitute is typically provided in pure, solid form (e.g.,granular or powdered form). In certain embodiments, the sugar substituteis dry, comprising a very low water content. For example, the sugarsubstitute can comprise less than about 5% water by weight, less thanabout 3% water by weight, less than about 2% water by weight, or lessthan about 1% water by weight.

The sugar substitute can be any sugarless material (i.e., sucrose-freematerial) and can be natural or synthetically produced. The sugarsubstitute used in the invention can be nutritive or non-nutritive. Forexample, the sugar substitute is commonly a sugar alcohol. Sugaralcohols that may be useful according to the present invention include,but are not limited to, erythritol, threitol, arabitol, xylitol,ribotol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol,lactitol, polyglycitol, and mixtures thereof. For example, in certainembodiments, the sugar alcohol is selected from the group consisting oferythritol, sorbitol, and isomalt.

In certain embodiments, the sugar substitute is capable of forming aglassy matrix. The formation of a glassy matrix is commonlycharacterized by a translucent/transparent appearance. Typically, thesugar substitute is substantially non-hygroscopic. Non-hygroscopicmaterials typically do not absorb, adsorb, and/or retain a significantquantity of moisture from the air. For example, in some embodiments, thesugar substitute exhibits a weight gain of water of less than about 50%upon exposure to conditions of 25° C., 80% relative humidity for twoweeks. Typically, the sugar substitute exhibits a weight gain of lessthan about 30%, less than about 20%, less than about 10%, less thanabout 5%, less than about 2%, or less than about 1% upon exposure toconditions of 25° C., 80% relative humidity for two weeks.Non-hygroscopic materials can provide the benefit of reducing thetendency of the nicotine-containing product to tackify upon exposure tohumidity.

In certain embodiments, the sugar substitute comprises one or more sugaralcohols. For example, in one embodiment, the sugar substitute isisomalt. Isomalt is a disaccharide that is typically made by enzymaticrearrangement of sucrose into isomaltulose, followed by hydrogenation togive an equimolar composition of 6-O-α-D-glucopyranosido-D-sorbitol(1,6-GPS) and 1-O-α-D-glucopyranosido-D-mannitol-dihydrate(1,1-GPM-dihydrate).

In addition to the nicotinic compound and sugar substitute, thenicotine-containing product of the present invention typically containsa syrup, e.g., a sugar syrup or a sugar alcohol syrup. “Sugar alcoholsyrup” as used herein is intended to refer to a thick solution of sugaralcohol in water, e.g., having greater than about 40% solids, preferablyhaving greater than about 50% solids, greater than about 60% solids,greater than about 70% solids, or greater than about 80% solids, byweight. Typically, the solid content of the sugar alcohol syrupprimarily comprises the named sugar alcohol (i.e., maltitol syruptypically comprises greater than about 80%, greater than about 85%, orgreater than about 90% by weight maltitol on a dry basis). Sugar alcoholsyrups are generally prepared by heating a solution of the sugar alcoholin water and cooling the mixture to give a viscous composition. Theresulting syrup is typically characterized by a relatively highconcentration of sugar alcohol and relatively high stability (i.e., thesugar alcohol typically does not crystallize from solution, e.g., atroom temperature).

The syrup, e.g., sugar alcohol syrup, desirably is capable of affectingthe re-crystallization of a melted sugar substitute. One exemplary sugaralcohol syrup that is particularly useful according to the presentinvention is maltitol syrup. Other sugar alcohol syrups can be used,including, but not limited to, syrups containing xylitol, mannitol,glycerol, erythritol, threitol, arabitol, ribitol, mannitol, sorbitol,dulcitol, iditol, isomalt, lactitol, or polyglycitol. Such sugar alcoholsyrups can be prepared or can be obtained from commercial sources. Forexample, maltitol syrups are commercially available from such suppliersas Corn Products Specialty Ingredients of Newark, Delaware. Althoughsugar alcohol syrups may be preferred, sugar syrups can, in certainembodiments, be used in place of or in combination with the sugaralcohol syrup. For example, in some embodiments, corn syrup, goldensyrup, and/or molasses can be used.

The amount of sugar alcohol syrup added to the product mixture istypically that amount required to slow recrystallization of the sugarsubstitute in melted form. One of skill in the art would understand theneed to vary the amount of sugar alcohol syrup depending on thecomposition of the remaining ingredients to ensure that therecrystallization is sufficiently slow to provide a material with thedesired characteristics (e.g., a desired level oftranslucency/transparency). Accordingly, the amount of sugar alcoholsyrup can vary, but typically ranges from about 0.1% to about 2%, oftenfrom about 0.5% to about 1.5%, and more often about 1% by weight of thenicotine-containing product mixture. In certain embodiments, the amountof sugar alcohol syrup is higher, for example, up to about 2% by weightof the mixture, up to about 5% by weight of the mixture, up to about 10%by weight of the mixture, or up to about 20% by weight of the mixture.

Other pharmaceutically acceptable components may be added to theproducts of the invention. For example, in certain embodiments, thenicotine-containing pharmaceutical composition further comprises a salt.The presence of a salt in the composition may act to suppress bitternessand/or enhance sweetness. Any type of salt can be used. Common tablesalt (NaCl) is typically used according to the present invention, butother types of salts are intended to be encompassed as well. The amountof salt added may vary, but typically ranges from 0% to about 8%, forexample from about 1% to about 4% or from about 0% to about 2%, oftenaround 1% by weight of the pharmaceutical composition mixture. In someembodiments, a somewhat salty taste is a desirable feature of thepharmaceutical composition.

In some embodiments, the composition according to the invention furthercomprises one or more buffering agents and/or pH adjusters (e.g., acidsor bases). Certain exemplary buffering agents and/or pH adjustersinclude, but are not limited to, magnesium oxide, magnesium hydroxide,potassium carbonate, sodium carbonate, potassium bicarbonate, sodiumbicarbonate, or mixtures thereof. In some embodiments, one or morebuffering agents and/or pH adjusters are added to the mixture to ensurethat the final pharmaceutical composition has a pH within a desirablerange. Exemplary pH ranges in such compositions are generally from about6-11, and often about 7-10 (e.g., about 7 or about 8). In suchembodiments, the amount of buffering agent and/or pH adjuster added tothe composition mixture is simply that amount required to bring theformulation to, or keep the formulation at, the desired pH. The amountof buffering agent and/or pH adjuster added to any given formulation canbe readily calculated by one skilled in the art and may comprise, forexample, about 0.5% to about 1% by weight of the mixture. It is notedthat in certain embodiments, a basic pH is not necessary in the productsof the present invention. Accordingly, certain products of the presentinvention have a pH of less than about 6 or less than about 5 (e.g.,from about 4 to about 6).

Various food-grade buffering agents are known and can be used to adjustthe pH of the products of the present invention. Suitable bufferingagents include those selected from the group consisting of acetates,glycinates, phosphates, glycerophosphates, citrates such as citrates ofalkaline metals, carbonates, hydrogen carbonates, and borates, andmixtures thereof. In certain embodiments, the buffering agent is anamino acid, as taught for example, in US Pat. Pub. No. 2008/0286341 toAndersson et al. and PCT Appl. No. WO2008/040371 to Andersson et al.,which are both incorporated herein by reference. As noted therein,various amino acids and salts thereof are useful for this purpose,including, but not limited to, arginine, asparigine, glutamic acid,glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, serine, threonine, valine, cysteic acid, N-glycylglycine,and ornithine. In certain embodiments, N-glycylglycine or L-lysine isadded as a buffering agent. In some embodiments, an amino acid bufferingagent is used in combination with another amino acid buffering agentand/or in combination with one or more non-amino acid buffering agents.In certain embodiments, the optional pH adjusting agent is a base (e.g.,NaOH). In certain embodiments, L-lysine and NaOH are added to thecompositions of the present invention.

In some embodiments, one or more additional sweeteners are added to thecompositions of the present invention. The one or more additionalsweeteners can comprise any natural or artificial sweetener, including,but not limited to, sugar or any of the sugar substitutes describedpreviously. In certain embodiments, the sweetener can include,glycyrrhizin, glycerol, inulin, lactitol, lactose, mabinlin, maltitol,mannitol, miraculin, monatin, monellin, osladin, pentadin, polydextrose,sorbitol, stevia, tagatose, thaumatin, acesulfame potassium, alitame,aspartame, cyclamate, dulcin, glucin, neotame, saccharin, sorbitol,sucralose, xylitol, and combinations thereof. In certain embodiments,the sweetener comprises sucralose(1,6-Dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside).The amount of sweetener added can vary, but is typically that amountrequired for a sufficiently “sweet” taste. For example, sweetener can beadded to make the sweetness of the nicotine-containing pharmaceuticalcomposition comparable to that of sugar. In particular embodiments,sucralose is added in an amount of about 0.5% to about 2% by weight ofthe product mixture, often in an amount of about 1% by weight of themixture.

Various natural and/or artificial flavorants can also be added to thepharmaceutical compositions of the present invention, and the characterof these flavors can be described as, without limitation, fresh, sweet,herbal, confectionary, floral, fruity or spicy. Specific types offlavors include, but are not limited to, vanilla (e.g., vanillinoptionally in complexed form), coffee, chocolate, cream, mint,spearmint, menthol, peppermint, wintergreen, lavender, cardamon, nutmeg,cinnamon, clove, cascarilla, sandalwood, honey, jasmine, ginger, anise,sage, licorice, and fruit flavors such as lemon, orange, apple, peach,lime, cherry, and strawberry. See also, Leffingwill et al., TobaccoFlavoring for Smoking Products, R. J. Reynolds Tobacco Company (1972),which is incorporated herein by reference. Flavorings also can includecomponents that are considered moistening, cooling or smootheningagents, such as eucalyptus. Flavorings can also include sensates, whichcan add a range of tactile, organoleptic properties to thepharmaceutical compositions. For example, sensates can provide awarming, cooling, or tingling sensation. These flavors may be providedneat (i.e., alone) or in a composite (e.g., spearmint and menthol, ororange and cinnamon). Flavorants of this type can be present in anamount of from about 0.5% to about 15%, often between about 0.5% andabout 1.5% by weight of the mixture. In certain embodiments, theflavorant is present in any amount of at least about 0.5% by weight orat least about 0.75% by weight of the mixture.

It is well-known that nicotine is subject to oxidation and accordingly,it may be advantageous to incorporate one or more anti-oxidants, suchas, e.g., ascorbyl palmitate and/or sodium ascorbate, in a compositionaccording to the invention. The one or more anti-oxidants may be presentin a concentration of from about 0.05% to about 0.3% by weight, such as,e.g., from about 0.1% to about 0.25% or from about 0.15% to about 0.2%in the pharmaceutical composition mixture.

Various other substances can be added to the compositions of the presentinvention. For example, excipients such as fillers or carriers foractive ingredients (e.g., calcium polycarbophil, microcrystallinecellulose, hydroxypropylcellulose, sodium carboxymethylcellulose,cornstarch, silicon dioxide, calcium carbonate, lactose, and starchesincluding potato starch, maize starch, etc.), thickeners, film formersand binders (e.g., hydroxypropyl cellulose, hydroxypropylmethylcellulose, acacia, sodium alginate, xanthan gum and gelatin),antiadherents (e.g., talc), glidants (e.g., colloidal silica),humectants (e.g., glycerin), preservatives and antioxidants (e.g.,sodium benzoate and ascorbyl palmitate), surfactants (e.g., polysorbate80), dyes or pigments (e.g., titanium dioxide or D&C Yellow No. 10), andlubricants or processing aids (e.g., calcium stearate or magnesiumstearate) are added to the compositions in certain embodiments.

Certain types of nicotine-containing products also can have outercoatings composed of ingredients capable of providing acceptable outercoatings (e.g., an outer coating can be composed of ingredients such ascarnauba wax, and pharmaceutically acceptable forms of shellacs, glazingcompositions and surface polish agents). Application of a coating can beaccomplished using techniques such as airless spraying, fluidized bedcoating, use of a coating pan, or the like. Materials for use as acoating can be polymeric in nature, such as cellulosic material (e.g.,cellulose butyrate phthalate, hydroxypropyl methylcellulose phthalate,and carboxymethyl ethylcellulose), and polymers and copolymers ofacrylic acid, methacrylic acid, and esters thereof.

Formulations of the present invention may include short-term,rapid-onset, rapid-offset, controlled release, sustained release,delayed release, and pulsatile release formulations, providing theformulations achieve administration of a nicotinic compound as describedherein. See Remington's Pharmaceutical Sciences (18^(th) ed.; MackPublishing Company, Eaton, Pa., 1990), which is incorporated herein byreference in its entirety.

For example, solid dosage forms may be formulated so as to provide adelayed release of the active agent (i.e., the nicotinic compound), suchas by application of a coating. Delayed release coatings are known inthe art, and dosage forms containing such may be prepared by any knownsuitable method. Such methods generally include that, after preparationof the solid dosage form (e.g., a tablet or caplet), a delayed releasecoating composition is applied. Solid dosage forms according to thepresent invention may also be sustained release (i.e., releasing theactive agent over a prolonged period of time), and may or may not alsobe delayed release. Sustained release formulations are known in the artand are generally prepared by dispersing an active agent within a matrixof a gradually degradable or hydrolyzable material, such as an insolubleplastic, a hydrophilic polymer, or a fatty compound. Alternatively, asolid dosage form may be coated with such a material.

Compositions can be co-extruded, laminated or formed so as to havesandwich-type forms; and hence the location of nicotine and otheringredients can be controlled in order to provide the desired featuressuch as performance, behavior, interaction or non-interaction with otheringredients, storage stability, and the like. In addition, mixtures ofcomponent ingredients can be formulated and manufactured into core/shelltypes of configurations (e.g., lozenge types of products that have aninner region and at least one additional overlayer), with the variousregions of such products having differing overall compositions orproperties. Thus, for example, the nicotinic compound can have arelatively high concentration towards the inner region of the product,or a relatively high concentration towards the outer region of theproduct.

One particularly preferred type of a representative compositionincorporating nicotine as an active ingredient, and that comprisesnicotine in an orally provided form, has the form of a lozenge, tablet,microtab, or other tablet-type product. See, for example, the types ofnicotine-containing lozenges, lozenge formulations, lozenge formats andconfigurations, lozenge characteristics and techniques for formulatingor manufacturing lozenges set forth in U.S. Pat. Nos. 4,967,773 to Shaw;5,110,605 to Acharya; 5,733,574 to Dam; 6,280,761 to Santus; 6,676,959to Andersson et al.; 6,248,760 to Wilhelmsen; and 7,374,779; US Pat.Pub. Nos. 2001/0016593 to Wilhelmsen; 2004/0101543 to Liu et al.;2006/0120974 to Mcneight; 2008/0020050 to Chau et al.; 2009/0081291 toGin et al.; and 2010/0004294 to Axelsson et al.; which are incorporatedherein by reference.

The amount of the composition of the invention contained within eachpiece or unit of lozenge type of product can vary. For example, arepresentative unit for lozenge products generally weighs at least about100 mg, often at least about 200 mg, and frequently at least about 300mg; while the weight of a representative unit for such productsgenerally does not exceed about 1.5 g, often does not exceed about 1 g,and frequently does not exceed about 0.75 g.

The amount of active ingredient within the overall composition can vary.For a composition intended for oral consumption by insertion into themouth of the subject (e.g., a lozenge or the like), the amount ofnicotine within each dosage piece or unit typically is at least about0.5 mg, generally is at least 1 mg, often is at least about 1.5 mg, andfrequently is at least about 2 mg; while the amount of nicotine withineach piece typically does not exceed about 10 mg, generally does notexceed about 8 mg, often does not exceed about 6 mg, and frequently doesnot exceed about 5 mg, calculated as nicotine base. Exemplary types ofsuch products can incorporate about 2 mg, about 2.5 mg, about 3 mg,about 3.5 mg and about 4 mg of nicotine per piece or unit, calculated asnicotine base.

Compositions of the present invention incorporate a pharmaceuticallyeffective amount of nicotine. The dose of active ingredient (i.e., allthe various nicotine forms) is preferably that amount effective to treatsome symptoms of, or prevent occurrence of the symptoms of, thecondition, disease, or disorder from which the subject or patientsuffers. By “effective amount”, “therapeutic amount” or “effective dose”is meant that amount sufficient to elicit the desired pharmacological ortherapeutic effects, thus resulting in effective prevention or treatmentof the condition, disease, or disorder. Thus, an effective amount ofactive ingredient is an amount sufficient to enter relevant regions ofthe body (e.g., to pass across the blood-brain barrier of the subject),to bind to relevant receptor sites in the CNS and PNS of the subject,and/or to elicit neuropharmacological effects (e.g., elicitneurotransmitter secretion, thus resulting in effective prevention ortreatment of the condition, disease, or disorder). Prevention of thedisorder is manifested, for example, by delaying the onset of thesymptoms of the condition, disease, or disorder. Treatment of thedisorder is manifested by, for example, a decrease in the symptomsassociated with the condition, disease, or disorder or an ameliorationof the reoccurrence of the symptoms thereof.

For compositions of the present invention, the intended daily dose ofthe active ingredient can vary. The overall dose of active ingredientcan depend upon factors such as the weight of the subject ingesting thecomposition, the condition being treated, the state or severity of thedisease or disorder being treated, the desired pharmacological effect,or other such factors. Typically, the amount of nicotine activeingredient, calculated as nicotine base, administered to a subject perday is at least about 2 mg, often is at least about 4 mg, and frequentlyis at least about 10 mg. Typically, the amount of nicotine activeingredient administered to a subject per day does not exceed about 60mg, often does not exceed about 50 mg, and frequently does not exceedabout 40 mg. See also, for example, the types of dosing regimens andadministration techniques set forth in U.S. Pat. Nos. 5,593,684 to Bakeret al.; 6,660,754 to Kyle et al.; and US Pat. Pub. Nos. 2004/0006113 toSachs; 2005/0214229 to Pinney et al.; 2008/0124283 to Andersen; and2009/0293895 to Axelsson et al.; which are incorporated herein byreference.

Representative compositions incorporating nicotine as an activeingredient can have various types of formats and configurations, and asa result, the character, nature, behavior, consistency, shape, form,size and weight of the composition can vary. The shape of arepresentative composition can be generally spherical, cylindrical(e.g., ranging form the general shape of a flattened disc to the generalshape of a relatively long, slender stick), helical, obloid, square,rectangular, or the like; or the composition can have the form of abead, granular powder, crystalline powder, capsule, film, strip, gel, orthe like. The shape of the composition can resemble a wide variety ofpill, tablet, lozenge, capsule, caplet, pouch and gum types of productsthat traditionally have been employed for the administration ofpharmaceutical types of products. The general nature of a representativecomposition can be soft or hard to the feel, or of intermediate softnessor hardness; and as such, the composition can be considered to bemalleable, flexible, chewy, resilient, brittle, or the like. Whenadministered orally, various components of the product can be consideredto be readily dispersible or slow to disperse, or those variouscomponents can dissolve at varying rates (e.g., from relatively fast torelatively slow). As a result, for compositions ingested by insertion inthe mouth of the human subject, the release rate of active ingredientduring use of the product can vary from relatively fast to relativelyslow, depending upon factors such as the design of the product and theuse of product by the subject using that product. See also, by way ofexample, the types of products proposed in U.S. Pat. Nos. 4,655,231 toRay et al.; 5,147,654 to Place et al.; 5,543,424 to Carlsson et al.;6,268,386 to Thompson; 6,319,510 to Yates; 6,488,953 Halliday et al.;6,709,671 to Zerbe et al.; 7,025,983 to Leung et al.; 7,105,173 toRolling; 7,115,297 to Stillman; 7,435,749 to Knight; and 7,491,406 toLeung et al.; and US Pat. Pub. Nos. 2006/0198873 to Chan et al.;2006/0240087 to Houze et al.; 2006/0204559 to Bess et al.; 2007/0269492to Steen et al.; 2008/0020050 to Chau et al.; 2008/0286340 to Anderssonet al.; 2008/0292683 to Sanghvi et al.; and 2009/0004248 to Bunick etal.; which are incorporated herein by reference.

In certain embodiments, the nicotine-containing pharmaceuticalcomposition is transparent or translucent as defined herein.Transparency/translucency can be determined by any means commonly usedin the art; however, it is commonly measured by spectrophotometric lighttransmission over a range of wavelengths (e.g., from about 400-700 nm).Transmission measurements for the nicotine-containing products of thepresent invention are typically comparable to or higher than those oftraditional nicotine-containing products. Translucency can also beconfirmed by visual inspection by simply holding the product up to alight source and determining if light travels through the product in adiffuse manner.

The manners and methods used to formulate and manufacture thenicotine-containing composition can vary. Typical conditions associatedwith manufacture of pharmaceutical types of products include control ofheat and temperature (i.e., the degree of heat to which the variousingredients are exposed during manufacture and the temperature of themanufacturing environment), moisture content (e.g., the degree ofmoisture present within individual ingredients and within the finalcomposition), humidity within the manufacturing environment, atmosphericcontrol (e.g., nitrogen atmosphere), airflow experienced by the variousingredients during the manufacturing process, and other similar types offactors. Additionally, various process steps involved in productmanufacture can involve selection of certain solvents and processingaids, use of heat and radiation, refrigeration and cryogenic conditions,ingredient mixing rates, and the like. The manufacturing conditions alsocan be controlled due to selection of the form of various ingredients(e.g., solid, liquid, or gas), particle size or crystalline nature ofingredients of solid form, concentration of ingredients in liquid form,or the like. Ingredients can be processed into the desired compositionby techniques such as extrusion, compression, spraying, and the like.

For example, the compositions can be prepared via any method commonlyused for the preparation of hard boiled confections. Exemplary methodsfor the preparation of hard confections can be found, for example, inLFRA Ingredients Handbook, Sweeteners, Janet M. Dalzell, Ed.,Leatherhead Food RA (December 1996), pp. 21-44, which is incorporatedherein by reference.

Typically, the products of the invention are prepared by first preparinga first mixture of ingredients. The composition of the first mixture ofingredients can vary; however, it typically comprises a sugar substituteand may contain various optional additional substances (e.g., the sugaralcohol syrup, NaCl, preservatives, further sweeteners, water, and/orflavorings). In certain embodiments, the first mixture of ingredientscomprises the sugar substitute and sugar alcohol syrup (e.g., maltitolsyrup or xylitol syrup). Typically, the first mixture of ingredientsdoes not contain the nicotinic compound.

The first mixture of ingredients is heated until it melts; subsequently,the mixture is heated to or past the hard crack stage. In confectionarymaking, the hard crack stage is defined as the temperature at whichthreads of the heated mixture (obtained by pulling a sample of cooledsyrup between the thumb and forefinger) are brittle or as thetemperature at which trying to mold the syrup results in cracking.According to the present method, the temperature at which the hard crackstage is achieved can vary, depending on the specific makeup of theproduct mixture but generally is between about 145° C. and about 170° C.(e.g., about 165° C.). Typically, the mixture is not heated above about171° C., which is the temperature at which caramelization begins tooccur. In the processes of the present invention, the mixture istypically heated to the hard crack stage temperature or above and thenallowed to cool. The heating can be conducted at atmospheric pressure orunder vacuum. Typically, the method of the present invention isconducted at atmospheric pressure.

In one exemplary embodiment, the first mixture of ingredients comprisesa high percentage of isomalt and the mixture is heated past the hardcrack stage (e.g., to about 165° C.). The mixture is heated to thistemperature and then removed from the heat to allow the mixture to cool.At one or more predetermined temperatures, certain additional componentsare added. For example, in certain embodiments, various components areadded when the melt has cooled to about 143° C. For example, certaincomponents that may be added at this point include, but are not limitedto, buffers, water, and/or the nicotinic compound. In some embodiments,various components are added when the melt has cooled to about 120° C.For example, certain components that may be added at this point include,but are not limited to, flavorants, the nicotinic compound, water,and/or sweeteners. Certain flavorants are volatile and are thuspreferably added after the mixture has cooled somewhat. Further, in someembodiments, it is desirable to add the tobacco component at a somewhatcooled temperature. As noted above, in certain embodiments, variouscomponents are added at different stages in the cooling process.However, it is also possible to combine these components and add themtogether at a single stage in the cooling process.

The combined mixture is then formed into the desired shape. In certainembodiments, the mixture is poured directly into molds, formed (e.g.,rolled or pressed) into the desired shape, or extruded. If desired, themixture can be extruded or injection molded. In certain embodiments, themixture is formed or extruded into a mold of desired shape in anenclosed system, which may require decreased temperature and which maylimit evaporation of certain mixture components. For example, such asystem may limit the evaporation of volatile components including, butnot limited to, the nicotinic compound and/or flavorants. Other methodsof producing nicotine-containing products such as lozenges are alsointended to be encompassed herein. In use, the compositions of thepresent invention are typically administered in a form adapted forbuccal or sublingual delivery. In certain embodiments, the compositionsare in a form suitable for oral ingestion. For example,nicotine-containing compositions can be administered and employed usingthe manners and methods typically used for the administration oftraditional types of nicotine-containing lozenges.

The compositions of the present invention can be used for treatment of awide variety of conditions, diseases, and disorders responsive tostimulation of one or more types of nicotinic acetylcholinergicreceptors (nAChRs). The compositions can be used to treat those types ofconditions, diseases, and disorders that have been reported to betreatable through the use or administration of nicotine as an agonist ofnAChRs. As such, the compositions can be used to treat various CNSconditions, diseases, and disorders, and the compositions also can beused as smoking cessation aids (i.e., as components of NRT). Exemplaryconditions, diseases or disorders that can be treated include cognitivedisorders such as Alzheimer's disease and attention deficit disorder,schizophrenia, Parkinson's disease, Tourette's syndrome, ulcerativecolitis, dry eye disease, hypertension, obesity, and hemorrhoids.Compositions of the invention may also find use as a treatment to reducestress or pain.

Many modifications and other embodiments of the invention will come tomind to one skilled in the art to which this invention pertains havingthe benefit of the teachings presented in the foregoing description.Therefore, it is to be understood that the invention is not to belimited to the specific embodiments disclosed and that modifications andother embodiments are intended to be included within the scope of theappended claims. Although specific terms are employed herein, they areused in a generic and descriptive sense only and not for purposes oflimitation.

Aspects of the present invention are more fully illustrated by thefollowing examples, which are set forth to illustrate certain aspects ofthe present invention and are not construed as limiting thereof.

EXPERIMENTAL

The following examples are provided in order to further illustrate theinvention but should not be construed as limiting the scope thereof.Unless otherwise noted, all parts and percentages are by weight.

Hard-boiled lozenges are prepared according to the following process.Isomalt and maltitol syrup (or xylitol syrup) are heated to meltingwithout stirring, to hard crack temperature (e.g., 165° C.). The melt iscooled to approximately 143° C., with very slight, discontinuousstirring. Other components (e.g., buffer, nicotine, sweetener, and/orflavorants) are added to the mixture and folded in carefully with aspatula without introducing much air into the melt. The melt is furthercooled to about 120° C. Further components (e.g., buffer, nicotine,sweetener, and/or flavorants) are added to the mixture and folded incarefully with a spatula without introducing much air into the melt. Thefinal mixture is poured into a glass beaker, the contents are pouredfrom the beaker in a chord on a metal brick, in breakaway molds withniches of suitable dimensions, or in molds (for individual lozenges). Itmay be necessary to reheat the beaker in order to obtain a viscosity ofthe melt so it flows easily. The melt is cooled for a time suitable forsolidifying (e.g., at room temperature).

Table 1 below provides six examples of product compositions preparedaccording to the invention as outlined above.

TABLE 1 Formulations of Samples 1-6 Sample 1 Sample 2 Sample 3 Sample 4Sample 5 Sample 6 Component (g) (g) (g) (g) (g) (g) Isomalt 279.6 279.6278.8 279.6 281.85 278.85 Maltitol syrup 15.0 15.0 15.0 — 15.0 — Sodiumcarbonate 2.25 2.25 2.25 2.25 — 2.25 Acesulfame K 0.15 0.15 0.15 0.150.15 0.15 Mint-derived Flavorant 0.75 0.75 0.75 0.75 0.75 1.5 PeppermintFlavorant 0.75 0.75 — — — 0.75 Mint Flavorant — — 1.5 0.75 0.75 — Water7.75 + 10* 4 — 4 4 4 Nicotine bitartrate dihydrate 1.5 1.5 1.5 1.5 1.51.5 Xylitol syrup — — — 15.0 — 15.0 *Added in two separate process stepsas provided in Table 2, below (7.75 g added in Addition, 1, 10 g addedin Addition 2)

In Table 2 below, each of the six samples is described in terms ofprocess steps used to produce the product. The steps including the stepof forming a first mixture (e.g., Isomalt and maltitol syrup), meltingthe first mixture at a temperature above the hard crack stage, coolingthe first mixture to about 143° C. and then adding a second compositionto the first mixture (i.e., Addition 1 in the table), and finallycooling the product mixture to 120° C. before adding the finalingredients (i.e., Addition 2 in the table).

TABLE 2 Preparation of Sample 1-6 Process step Sample 1 Sample 2 Sample3 Sample 4 Sample 5 Sample 6 Melt Isomalt, Isomalt, Isomalt, Isomalt,Isomalt, Isomalt, maltitol maltitol maltitol xylitol maltitol xylitolsyrup syrup, syrup, syrup, syrup syrup, sodium sodium sodium sodiumcarbonate carbonate carbonate carbonate Cooling to yes yes yes yes yesyes 143° C. Addition 1 Sodium — Nicotine Nicotine Nicotine Nicotinecarbonate, bitartrate bitartrate bitartrate bitartrate water dihydratedihydrate, dihydrate, dihydrate, water water water Cooling to yes yesyes yes yes yes 120° C. Addition 2 Nicotine Nicotine AcesulfameAcesulfame Acesulfame Acesulfame bitartrate bitartrate K, Cooling K,Cooling K, Cooling K, Cooling dihydrate, dihydrate, Flavorant,Flavorant, Flavorant, Flavorant, water, water, Mint Mint Mint Peppermintacesulfame acesulfame Flavorant Flavorant Flavorant Flavorant K, CoolingK, Cooling Flavorant Flavorant, Peppermint Peppermint FlavorantFlavorant Appearance Brown Brown Brown, Brown Slightly Brown(translucent opaque yellow unless otherwise described)

1. A nicotine-containing pharmaceutical composition, comprising: a. anicotinic compound; b. a sugar substitute in an amount of at least about80% by weight; and c. a sugar alcohol syrup, wherein the sugarsubstitute is a non-hygroscopic sugar alcohol capable of forming aglassy matrix and wherein the composition is in a pharmaceuticallyacceptable form adapted for oral delivery of the composition.
 2. Thepharmaceutical composition of claim 1, wherein at least a portion of thenicotinic compound is in the form of a free base, a salt, a complex, ora solvate.
 3. The pharmaceutical composition of claim 2, wherein thenicotinic compound is nicotine polacrilex.
 4. The pharmaceuticalcomposition of claim 1, wherein the nicotinic compound is sorbed onto aporous particulate carrier.
 5. The pharmaceutical composition of claim4, wherein the porous particulate carrier comprises microcrystallinecellulose.
 6. The pharmaceutical composition of claim 1, wherein thesugar substitute is isomalt.
 7. The pharmaceutical composition of claim1, wherein the sugar alcohol syrup is in an amount sufficient to slowrecrystallization of the sugar substitute in melted form.
 8. Thepharmaceutical composition of claim 1, wherein the sugar alcohol syrupis maltitol syrup or xylitol syrup.
 9. The pharmaceutical composition ofclaim 1, wherein the composition comprises at least about 85% by weightof the sugar substitute.
 10. The pharmaceutical composition of claim 1,wherein the composition comprises at least about 4.0% by weight of sugaralcohol syrup.
 11. The pharmaceutical composition of claim 1, whereinthe composition comprises at least about 4.5% by weight of sugar alcoholsyrup.
 12. The pharmaceutical composition of claim 1, wherein thecomposition is in the form of a lozenge or tablet.
 13. Thepharmaceutical composition of claim 1, wherein the composition istranslucent.
 14. The pharmaceutical composition of claim 1, wherein thecomposition further comprises one or more flavorants.
 15. Thepharmaceutical composition of claim 14, wherein the amount of flavorantis from about 0.1 to about 0.5 percent by weight of the pharmaceuticalcomposition.
 16. The pharmaceutical composition of claim 14, wherein theflavorant is vanillin and/or mint flavor.
 17. The pharmaceuticalcomposition of claim 1, further comprising at least one sweetener. 18.The pharmaceutical composition of claim 17, wherein the at least onesweetener comprises sucralose.
 19. The pharmaceutical composition ofclaim 1, further comprising NaCl.
 20. The pharmaceutical composition ofclaim 19, wherein the amount of NaCl is from about 0.5 to about 1percent by weight of the pharmaceutical composition.
 21. A method fortreating a human subject having a condition, disease, or disorderresponsive to stimulation of nicotinic acetylcholinergic receptors,comprising orally administering an effective amount of a pharmaceuticalcomposition according to claim 1 to said human subject.
 22. The methodof claim 21, wherein said administering step comprises administering thepharmaceutical composition to a human subject having a condition,disease, or disorder of the central nervous system.
 23. The method ofclaim 21, wherein said administering step comprises administering thepharmaceutical composition to a human subject as a smoking cessationaid.
 24. The method of claim 21, wherein the nicotinic compound isnicotine free base or nicotine polacrilex.
 25. The method of claim 21,wherein the nicotinic compound is sorbed onto a porous particulatecarrier.
 26. The method of claim 25, wherein the porous particulatecarrier comprises microcrystalline cellulose.
 27. The method of claim21, wherein the composition is in the form of a lozenge or tablet.
 28. Amethod of preparing a nicotine-containing pharmaceutical compositionaccording to claim 1, comprising: (i) mixing a non-hygroscopic sugarsubstitute capable of forming a glassy matrix in an amount of at leastabout 80% by weight and a sugar alcohol syrup in a melted state to forma mixture; (ii) cooling the mixture and incorporating a nicotiniccompound into the cooled mixture; and (iii) further cooling the mixtureto room temperature to form a solid nicotine-containing pharmaceuticalcomposition.
 29. The method of claim 28, wherein at least a portion ofthe nicotinic compound is in the form of a free base, a salt, a complex,or a solvate.
 30. The method of claim 28, wherein the nicotinic compoundis nicotine polacrilex.
 31. The method of claim 28, wherein thenicotinic compound is sorbed onto a porous particulate carrier.
 32. Themethod of claim 31, wherein the porous particulate carrier comprisesmicrocrystalline cellulose.
 33. The method of claim 28, wherein thesugar substitute is isomalt.
 34. The method of claim 28, wherein thesugar alcohol syrup is in an amount sufficient to slow recrystallizationof the sugar substitute in melted form.
 35. The method of claim 28,wherein the sugar alcohol syrup is maltitol syrup or xylitol syrup. 36.The method of claim 28, wherein the pharmaceutical composition comprisesat least about 85% by weight of the sugar substitute.
 37. The method ofclaim 28, wherein the pharmaceutical composition comprises at leastabout 4.0% by weight of sugar alcohol syrup.
 38. The method of claim 28,wherein the pharmaceutical composition comprises at least about 4.5% byweight of sugar alcohol syrup.
 39. The method of claim 28, wherein thecomposition is in the form of a lozenge or tablet.
 40. The method ofclaim 28, wherein the composition is translucent.
 41. The method ofclaim 28, further comprising adding one or more components selected fromthe group consisting of flavorants, sweeteners, and NaCl.
 42. The methodof claim 41, wherein the amount of flavorant is from about 0.1 to about0.5 percent by weight of the pharmaceutical composition.
 43. The methodof claim 41, wherein the flavorant is vanillin or mint flavor.
 44. Themethod of claim 41, wherein the sweetener comprises sucralose.
 45. Themethod of claim 41, wherein the amount of NaCl is from about 0.5 toabout 1 percent by weight of the pharmaceutical composition.
 46. Themethod of claim 28, wherein the mixing step comprises heating the sugarsubstitute and the sugar alcohol syrup to a temperature above the hardcrack stage of the sugar substitute and wherein the incorporating stepcomprises adding a nicotinic compound to the mixture at a temperaturebelow the hard crack stage of the sugar substitute.
 47. The method ofclaim 46, wherein the hard crack stage is about 145° C. to about 155° C.and the sugar substitute and the sugar alcohol syrup are heated at atemperature between the hard crack stage and about 171° C.